management information comprehensible to lawyers, politicians, judges, business and labor, environmentalists, and community groups.

24.2RISK ASSESSMENT METHODS

According to the National Research Council of the National Academy of Science, risk assessment consists of four broad but interrelated components: hazard identiﬁcation,dose-responseassessment, exposure assessment, and risk characterization, as depicted in Figure 24.1. The reader should, however, be aware that these risk assessment activities can provide research needs that improve the accuracy of estimating the “risk” or probability of an adverse outcome.

24.2.1Hazard Identiﬁcation

In this ﬁrst component of risk assessment, the question of causality in a qualitative sense in addressed; that is, the degree to which evidence suggests that an agent elicits

Dose-response

Assessment

Hazard

Exposure

Identification

Assessment

Risk

Characterization

Figure 24.1 Risk assessment paradigm as per NAS and US EPA.

RISK ASSESSMENT METHODS

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a given effect in an exposed population. Among many factors the quality of the studies and the severity of the health effects should be evaluated at this stage. The following are evaluated: (1) validity of the toxicity data, (2) weight-of-evidencesummary of the relationship between the substance and toxic effects, and (3) estimates of the generalizability of data to exposed populations. Where there are limited in vivo toxicity data,structural activity relationships (SARs) andshort-term assays may be indicative of a chemical hazard. Key molecular structures such asn-nitrosoor aromatic amine groups and azo dye structures can be used for prioritizing chemical agents for further testing. SARs are useful in assessing relative toxicity of chemically related compounds, but there are several limitations. For example, toxicity equivalent factors (TEFs) based on induction of Ah receptor by dioxins demonstrated that SARs may not always be predictive. In vitroshort-terminexpensive test such as bacterial mutation assays can helpidentify carcinogens, and there are othershort-termtests that can help identify chemicals that potentially can be associated with neurotoxicity, developmental effects, or immunotoxicity. Many of these in vitro studies can provide some insight into mechanism(s) of action, but there may be somefalse positives andfalse negatives. Animal studies are usuallyroute-speciﬁcand relevant to human exposure, and animal testing usually involves two species, both sexes, 50 animals/dose group, andnear-lifetimeexposures. Doses are usually 90, 50, and 10 to 25% of the maximum tolerated dose (MTD). In carcinogenicity studies, the aim is to observe signiﬁcant increases in number of tumors, induction of rare tumors, and earlier induction of observed tumors. However, rodent bioassays may not be predictive of human carcinogenicity because of mechanistic differences For example, renal tumors in male rats is associated withα2µ-globulin-chemicalbinding and accumulation leading to neoplasia; however,α2µ-globulinis not found in humans, mice, or monkeys. There are differences in susceptibility toaﬂatoxin-inducedtumors between rats and mice that can be explained by genetic differences in expression of cytochrome P450 and GST isoenzymes. Whereas humans may be as sensitive as rats toAFB1-inducedliver tumors, mice may not be predictive ofAFB1-inducedtumors in humans. Epidemiological data from human epidemiological studies are the most convincing of an association between chemical exposure and disease, and therefore can very useful for hazard identiﬁcation. Exposures are not often well deﬁned and retrospective, and confounding factors such as genetic variations in a population and human lifestyle differences (e.g., smoking) present a further challenge. The three major types of epidemiological studies available are (1)cross-sectional studies, which involve sampling without regard to exposure or disease status, and these studies identify risk factors (exposure) and disease but not useful for establishingcause-effectrelationships; (2)cohort studies, which involve sampling on the basis of exposure status, and they target individuals exposed and unexposed to chemical agent and monitored for development of disease, and these areprospective studies; (3)case-control studies, which involve sampling on the basis of disease status. These are retrospective studies, where diseased individuals are matched withdisease-freeindividuals.

24.2.2Exposure Assessment

This process is an integral part of the risk assessment process. However this will be introduced only brieﬂy in this chapter, and the reader is encouraged to consult Chapter 28 in this text as well as numerous other texts that describe the process in

426 HUMAN HEALTH RISK ASSESSMENT

more depth. In brief, exposure assessment attempts to identify potential or completed exposure pathways resulting in contact between the agent and at-riskpopulations. It also includes demographic analysis ofat-riskpopulations describing properties and characteristics of the population that potentiate or mitigate concern and description of the magnitude, duration, and frequency of exposure. The reader should be aware that exposure may be aggregate (single event added across all media) and/or cumulative (multiple compounds that share a similar mechanism of toxicity). Various techniques such as biomonitoring, model development, and computations can be used to arrive at an estimate of chemical dose taken up by humans, that is, chemical exposure. For example, the lifetime average daily dose (LADD) is a calculation for individuals exposed at levels near the middle of the exposure distribution:

Biological monitoring of blood and air samples represent new ways of reducing uncertainty in these extrapolations. For occupational exposures there are occupational exposure limits (OELs) that are guidelines or recommendations aimed at protecting the worker over their entire working lifetime (40 years) for 8 h/day, 5 days/week work schedule. Most OELs are presented as a time-weightedaverage concentration for an8-hourday for a40-hourwork week. There are threshold limit values (TLVs) that refer to airborne concentrations and conditions under which workers may be exposed daily but do not develop adverse health effects. Theshort-termexposure limit (STEL) are recommended when exposures are of short duration to high concentrations known to cause acute toxicity.

24.2.3Dose Response and Risk Characterization

Dose response is a quantitative risk assessment process, and primarily involves characterizing the relationship between chemical potency and incidence of adverse health effect. Approaches to characterizing dose-responserelationships include effect levels such as LD50, LC50, ED50, no observed adverse effect levels (NOAELs), margins of safety, therapeutic index. Thedose-responserelationship provides an estimation of the relationship between the dose of a chemical agent and incidence of effects in a population. Intuitively, a steepdose-responsecurve may be indicative of a homogeneous population response, while less steep or almost ﬂat slope may be indicative of greater distribution in response. In extrapolating from relatively high levels of exposure in experimental exposures (usually animals) to signiﬁcantly lower levels that are characteristic of the ambient environment for humans, it is important to note the shape of thedose-responsefunction below the experimentally observable range and therefore the range of inference. The shape of the slope may be linear or curvilinear and, it should be noted that the focus of risk assessment is generally on these lower regions of thedose-responsecurve (Figure 24.2).

There is a class of curvilinear dose-responserelationships in toxicological and epidemiological studies that may be described asU-shapedorJ-shaped curves. Other terms such as biphasic, and more recentlyhormesis, have been used to refer to paradoxical effects oflow-leveltoxicants. In brief, thesedose-responsecurves reﬂect an apparent improvement or reversal in the effect of an otherwise toxic agent. These